Project Summary/Abstract The overall objective of this Program Project is to define individual- and population-level immunological benchmarks for the prevention of dengue virus (DENV) infection and disease. Prevention of dengue is a high priority for the NIH and other organizations given its increasing medical and economic impact in both developing and developed countries. Dengue vaccine development has seen major progress, but encouraging results from efficacy trials have been offset by suboptimal efficacy and an increased risk for hospitalized dengue in some subpopulations. These results reinforce the need for research to fill gaps in current understanding of the determinants of the outcome of DENV infection. Critical elements for such research include capturing clinically-relevant endpoints, analyzing both natural infection and vaccination, and considering the epidemiologic context of infection. This program addresses this objective through synergistic epidemiologic, clinical, virologic, and immunologic investigations. Project 1 (Kamphaeng Phet Family Cohort Study) will extend surveillance of a household- based cohort of >3,000 individuals across the age spectrum to define correlates of risk over the course of sequential DENV exposures. Project 2 (Correlates of Protection and Risk in Dengue Transmission Clusters) will apply geographic cluster investigations to study correlates of risk in proximity to exposure and during the early phase of infection. Project 3 (Immunologic Determinants of Outcome in Dengue Virus Infection and Vaccination) will extend surveillance of a cohort of participants in a phase III dengue vaccine trial to analyze the evolution of immunological memory over time and its associations with outcome. The Administrative Core, Data Management and Statistics Core, and the Clinical Research Laboratory Core will provide essential scientific and fiscal oversight, coordinate data management and analysis, and provide laboratory infrastructure for specimen processing and testing, respectively, in support of all three Projects. As a whole, this program will: a) define immune responses to DENV at the individual level that are associated with the risk of infection and/or disease, capturing the full spectrum of previous DENV exposure, b) define immune responses that are associated with the risk of infection and/or disease after immunization with the licensed dengue vaccine, c) define immune responses at the population level that are associated with the risk of infection and/or disease in individual subjects, and d) determine the contribution of waning immunity after natural infection or vaccination to the risk of infection and/or disease. The program builds on concepts, techniques, and expertise established during previous periods, and its findings should have basic science as well as clinical and public health implications.